Coronary heart disease (CHD) remains a leading cause of death and disability worldwide, despite significant advances in both prevention and treatment. Approximately 32% of all deaths are attributable to cardiovascular disease and the bulk of these are due to CHD (7). Accordingly, effective prevention of CHD would have profound implications for global health. Epidemiological, genetic, pharmacological, and animal studies implicate elevated plasma levels of low density lipoprotein-cholesterol (LDL-C) as the primary cause of CHD, and clinical trials have consistently shown that reduction of plasma LDLC levels is an effective strategy to prevent the disease. Consequently, LDL-lowering now constitutes the cornerstone of CHD prevention programs. Although several effective LDL-lowering agents are available, new therapeutic options are needed since >25% of patients fail to reach treatment goals (8). A major objective of this proposed project is to identify new therapeutic targets for LDL-lowering.